WO2013110152A1 - Pharmaceutical compositions containing angiotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor axis activators for the treatment of ocular pathological conditions - Google Patents

Abstract

The present invention describes pharmaceutical compositions containing angiotensin-converting enzyme 2(ACE2)/angotensin-(1-7)[ANg-(1-7)]/Mas receptor axis and the use thereof for the treatment of ocular pathological conditions linked with an increase in intraocular pressure (IOP) and/or with degeneration of the retina and/or of the optic nerve, such as, for example, glaucoma and retinopathy, preferentially diabetic retinopathy. Such pharmaceutical compositions may be administered by any drug-administration route, preferentially via the oral, topical ocular, intraocular, periocular, conjunctival or intravenous routes, amongst others. The pharmaceutical forms used are, preferentially, solution, suspension, emulsion, capsule (hard or gelatin), tablet, gel, cream, lotion, film, microcapsule, nanocapsule, nanosphere, microsphere, nanoemulsion, microemulsion and/or liposomes.

Description

 PHARMACEUTICAL COMPOSITIONS CONTAINING ANGIOTENSIN 2 / ANGIOTENSIN- (1-7) / MAS RECEIVER CONVERTER AXIS ENGINE DRIVERS

 The present invention describes pharmaceutical compositions containing Angiotensin 2 (ECA2) / Angiotensin- (1-7) [Ang- (1-7)] / Receptor Axis Enzyme Axis Activators and their use in the treatment of related eye conditions. with increased intraocular pressure (IOP) and / or retinal and / or optic nerve degeneration such as glaucoma and retinopathy, preferably diabetic retinopathy. Such pharmaceutical compositions may be administered by any drug administration route, preferably oral, topical, intraocular, periocular, conjunctival or intravenous routes, among others. The pharmaceutical forms used are preferably solution, suspension, emulsion, capsule (hard or gelatinous), tablet, gel, cream, lotion, film, microcapsule, nanocapsule, nanosphere, microsphere, nanoemulsion, microemulsion and / or liposomes.

Glaucoma is a neurodegenerative disease characterized by progressive death of retinal ganglion cells and degeneration of the optic nerve. It is estimated that the disease affects more than 67 million people worldwide, being the third leading cause of partial vision loss and the second leading cause of blindness (Johnson TV, Tomarev SI. Rodent models of glaucoma. Brain Res. Buli. , v. 81, pp. 349-58, 2010; Cronemberger S, Lourenco LFS, Silva LC, Calixto, Pires MC Prognosis of glaucoma in relation to blindness at a university hospital Arq. Bras Oftalmol., v.72, n.2, pp. 199-204, 2009; Who. World Health Organization. WHO releases the new global estimates on visual impairment. 2010. Available at: <http://www.who.int/blindness/en/> Access on 2. Mar. 2011). Vision loss caused by glaucoma is irreversible, and in 2002 the disease accounted for 12.3% of the world's vision loss cases (Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet, v. 363, p.1711-1720, 2004; Resnikoff S, Pascolini D, Etya'ale D, Kocur I, Pararajasegaram R, Pokharel GP. Global data on visual impairment in the year 2002. Buli. World. Health Organ., V. 82, no. 11, p. 844-51, 2004).

Although several risk factors are associated with the development of glaucoma, such as age, ethnicity, myopia, family history, and central corneal thickness, elevated intraocular pressure (IOP) is considered to be the major risk factor for development and progression. of the disease (Pang LH, Clark AF. Rodent odels for Glaucoma Retinopathy and Optic Neuropathy. J. Glaucoma, v.16, p. 483-505, 2007). Elevated IOP becomes incompatible with normal optic nerve function and the optic nerve, when degenerating, causes progressive changes in the visual field, which can lead to blindness (Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet, v. 363, p.1711-1720, 2004). Regarding its origin, glaucoma may be congenital, primary or secondary to other pathologies. The most common manifestation of the disease is primary glaucoma. There are two main types of primary glaucoma: angle-closure (GPAF) and angle-closure (GPAA). In the first, there is a reduction in the angle of the anterior chamber of the eye causing obstruction of the passage of aqueous humor from the posterior to the anterior chamber through the pupil, usually due to an iris dilation (Lewis TL. Care of the Patient with open-angle . glaucoma ^2nd ed St. Louis.. American Optometric Association, 2002; Katzung BG Basic & Clinical pharmacology, 9 ^th ed New York: Lange Medical Books / McGraw Hill, p 216, 2004)... In GPAA, there is an impediment to drainage of aqueous humor through Schlemm's canals. It is a chronic disorder and over 75% of blindness is due to GPAA. The treatment of this type of glaucoma is mainly pharmacological and conventionally performed by the application of topical medication to reduce IOP. The most commonly used drugs include β-blockers, prostaglandin analogs, carbonic anhydrase inhibitors, selective α-2 agonists and cholinergic agents (Lewis TL. Care of the Patient with open-angle glaucoma. 2 ^nd ed. St. Louis: American Optometric Association, 2002; Mckinnon SJ, Goldberg LD, Peeples P, Walt JG, Bramley T. Current management of glaucoma and the need for complete therapy Am J. Manag Care, v. 14, no. 1, pp. S20-S27, 2008; Royai College of Ophthalmologists Guidelines for the management of open angle glaucoma and ocular hypertension. London, 2004. Available at: <http://www.rcophth.ac.uk/page.asp7sectionM51 & sectionTitle = Clinical + Guidelines>. Access on 2 mar. 201 1; Weinreb and Khaw, 2004). Since 2008, prostaglandin analogues have been considered one of the most effective and safe drugs for treating glaucoma. However, its high cost is a limiting factor in many cases (Parikh RS, Parikh SR, Navin S, Arun E, Thomas R. Practical approach to medical management of glaucoma. Indian J. Ophthalmol., V. 56, no. 3 , pp. 223-230, 2008).

Another group of conditions that can lead to impaired vision through retinal cell degeneration are retinopathies. One of the main retinopathies is diabetic. Currently, it is estimated that 7 to 8% of the world's population has diabetes mellitus (DM) (Bosco A, Lerário AC, Soriano D, Santos RF, Massote P, Galvão D, Franco AC, Purisch S, Ferreira AR. Retinopathy Endocrinol Metab., V.49, No. 2, pp. 217-227, 2005). In Brazil, DM is considered one of the major public health problems, being among the top 10 causes of mortality (Malerbi DA, Franco LJ. Multicenter study of the prevalence of diabetes mellitus and impaired glucose tolerance in the Urban Brazilian population. aged 30-69 (Diabetes Care, v. 15, pp. 1509-15, 1992). Diabetic retinopathy is one of the most common complications of DM and can be present in both type 1 and type 2 DM patients, becoming the most frequent cause of acquired blindness (Bosco A, Lerário AC, Soriano D, Santos RF). , Massote P, Galvao D, Franco AC, Purisch S, Ferreira AR Diabetic Retinopathy Arq Bras Endocrinol Metab, v.49, no 2, pp 217-227, 2005; Ferris III FL Diabetic retinopathy Diabetes Care, v. 16, pp. 322-5, 1993; Klein R, Klein BEK, Moss SE, Cruickshanks K. The Wisconsin Epidemiological Study of Diabetic Retinopathy Arch.Ophthamol, v. 12, pp 1217-28 Park SH, Park JW, Park SJ, et al., Apoptotic death of photoreceptors in the streptozotocin-induced retinal diabetic rat (Diabetologia, v. 46, pp. 1260-1268, 2003). Approximately 40,000 people worldwide become blind each year as a result of diabetic retinopathy. In addition, virtually all individuals with type 1 DM will progress to some form of retinopathy after 15 years of illness, of which approximately 60% will develop the most severe form, proliferative, whose characteristics involve irreversible loss of visual acuity, especially by traditional retinal detachment ( Bosco A, Lerário AC, Soriano D, Santos RF, Massote P, Galvao D, Franco AC, Purisch S, Ferreira AR Diabetic Retinopathy Arq. Bras Endocrinol Metab., V.49, n.2, p. 217 -227, 2005; Fong DS, Aiello LP, Ferris FL, Klein R. Diabetic retinopathy, Diabetes Care, v. 27, pp. 2540-53, 2004).

 Despite the traditional view related to the pathophysiology of diabetic retinopathy involving long-term microcirculatory damage, recent studies indicate that neuronal and glial cell damage may appear early in the disease (Mizutani M, Gerhardinger C, Lorenzi M. Muller). Diabetes, v. 47, pp. 445-449, 1998; Lorenzi M, Gerhardinger C. Early cellular and molecular changes induced by diabetes in the retina Diabetologia, v. 44, pp. 791-804 Park SH, Park JW, Park SJ, et al Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina Diabetologia, v. 46, pp. 1260-1268, 2003; Senanayake P, Drazba J, Shadrach K , Milsted A, Rungger-Brandle E, Nisbiyama K, Miura S, Karnik S, Sears JE, Hollyfield J. Angiotensin II and its receptor subtypes in the human retin Invest Invest Ophthalmol Vis Sei, v. 48, n. 7, pp. 3301-331, 2007). Since the retina is an integral part of the central nervous system and therefore uses glucose as the sole energy source for imaging and visual processing, hypoinsulinemia states with consequent hyperglycemia may alter visual function before injury. be clinically diagnosed.

Recent work has shown that Angiotensin II (Ang II), a well-known blood pressure control molecule, is also present in various retinal layers (ganglion cells, photoreceptor layer, endothelial cells and Muller cells) (Savaskan E, Loffler KU, Meier F, Muller S, Flammer J, Meyer P. Immunohistochemical localization of angiotensin II and AT1 receptor in human ocular tissues. Ophthalmic, v. 36, p. 312-320, 2004). With respect to Muller cells, Ang II appears to be involved in regulating vascular permeability and blood flow, and in forming and maintaining the blood-retinal barrier. The Muller cell is a very specialized cell and is the main retinal glial cell, spanning the full depth of this structure. As a result of this arrangement, these cells intersect between the vessels and neurons, playing an important role in glucose uptake from the circulation and energy transfer to the neurons (Park SH, Park JW, Park SJ, et al. Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina Diabetologia, v. 46, pp. 1 260-1268, 2003; Senanayake P, Drazba J, Shadrach K, Milsted A, Rungger-Brandle E, Nisbiyama K, Miura S, Karnik S, Sears JE, Hollyfield J. Angiotensin II and its receptor subtypes in the human retin Invest Invest Ophthalmol Vis Sci, v. 48, no 7, pp 3301-331, 2007).

 In 2000, a new enzyme from the Renin-Angiotensin System (SARS) was discovered, the Angiotensin-Converting Enzyme 2 (ECA2), which is homologous to the Angiotensin-Converting Enzyme (ACE). The main activity of ECA2 is the conversion of Ang II, which has vasoconstrictor and hypertensive activity, to the peptide Angiotensin- (1 - 7) [Ang- (1 -7)], which in turn has vasodilatory and antiproliferative activity (Chappell MC, Ferrario CM Angiotensin (1-7) in hypertension Curr Opin Opin Nephrol Hypertens, v. 8, no.2, pp 231-235,1999; Fyhrquist F, Saijonmaa O. Renin-angiotensin J. Intern. Med., v. 264, pp. 224-236, 2008; Imai Y, Kuba K, Ohto T., Penninger J. Angiotensin-Converting Enzyme 2 (ACE2) in Disease Pathogenesis. , v. 74, pp. 405-410, 201). To perform its functions, Ang- (1-7) binds to the membrane receptor Mas.

Drugs used to lower systemic blood pressure, such as ACE inhibitors, have also shown activity in reducing IOP (Hashimoto M, Silva MRBM, Neto, FJT. Effect of drugs used in treatment of systemic arterial hypertension on intraocular pressure: experimental study in dogs. Arq. Bras. Ophthalmol., V.65, p. 229-33, 2002; Mohamed R, Al-Sereiti, Turner, P. Effect of Captopril (an Angiotensin-Converting Enzyme Inhibitor) on Intraocular Pressure in Healthy Human Volunteers. J. Ocul. Pharmacol. Ther., V. 5, no. 1, p. 1-5, 1989). In addition, Ang II has been associated with the risk of developing both diabetic retinopathy and glaucoma (Sramek SJ, Wallow IH, Tewksbury DA, Brandt CR, Poulsen GL. An ocular renin-angiotensin system. Immunohistochemistry of angiotensinogen. Invest. Ophthalmol Vis. Sci., V. 33, pp. 1627-1632, 1992; Nadal JA, Scicli GM, Carbini LA, Nussbaum JJ, Scicli AG, Angiontensin II and retinal perieytes migration; Fong DS, Aiello LP, Ferris FL , Klein R. Diabetic retinopathy Diabetes Care, v. 27, pp. 2540-53, 2004; Hashizume K, Mashima Y, Fumayama T, Ohtake Y, Kimura I, Yoshida K, Yasuda N, Fujimaki T, Asaoka R, Koga T, Kanamoto T, Fukuchi T, Miyaki K. Genetic polymorphisms in the angiotensin II receptor gene and their association with open-angle glaucoma in a Japanese population Invest Ophthalmol Vis. Sci., V. 46, p. 1 993-2001, 2003). Thus, drugs capable of modulating the SARS, in addition to acting as potent antihypertensive drugs, may also act as hypotensive and antiproliferative drugs. Furthermore, activation of the ECA2 / Ang- (1-7) / Receptor axis may play an important role in ocular pathologies involving increased IOP and degeneration of retinal and / or optic nerve cells such as the glaucoma and retinopathies.

From the description of the ECA2 / Ang- (1-7) / Receptor Mas axis, molecules that act on its modulation, either via ECA2 activation or direct activation of the Mas receptors [Ang- (1-7) analogues] come from. being studied. The first non-peptide Ang- (1-7) analogue described (AVE 0991) was discovered in 2002 and had significant effects on vessels, kidneys and the heart, indicating its possible effect on the treatment of hypertension and cardiovascular disease (Santos RAS, Ferreira AJ, Pharmacological effects of AVE 0991, the nonpeptide angiotensin- (1-7) agonist receptor Cardiovasc. Rev., v. 24, p. 239-246, 2006). Other analogues identified were the CGEN-856S peptide and the thioether bridged-linked Ang- (1-7) cyclic [Ang- (1-7)] (Savergnini SQ, Beiman M, Lautner RQ, Paula-Carvalho V, Allahdadi K, DC Person, Costa-Fraga FP, Fraga-Silva RA, Cojocaru G, Cohen Y, Bader M., Almeida AP, Rotman G, Santos RAS Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Hypertension, v. 56, pp. 112-U174, 2010; KluskensLD, Nelemans AS, Rink R, of Vries L, Meter-Arkema A, Wang Y, Walther T, Kuipers A, Moll GN, Haas M. Angiotensin (1-7) with Thioether Bridge: An Angiotensin-Converting Enzyme-Resistant, Potent Angiotensin- (1-7) Analog J. Pharmacol Exp Ther, v. 328, pp 849-854, 2009).

 ECA2 activators have been developed as potential antihypertensive agents and from virtual scanning, xanthenone, 1 - [(2-dimethylamino) ethylamino] -4- (hydroxymethyl) -7 - [(4-methylphenyl) sulfonyloxy] - 9xanthen-9-one (XNT) and resorcinolnaphthalein have been identified as ECA2 activating agents. XNT exhibits in vivo activity in lowering blood pressure (Hernandez Prada JA, AJ Ferreira, Katovich MJ, Shenoy V, Qi Y, Santos RAS, Castellano RK, AJ Lampkins, Gubala V, Ostrov Mida. Structure-based Identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents (Hypertension, v. 51, pp. 1312-1317, 2008). Diminazene (DIZE) has also recently been identified as an ECA2 activator and potential precursor of new antihypertensive agents (Dasgupta, C, Zhang L. Angiotensin II receptors and drug discovery in cardiovascular disease. Drug Discov. Today, v. 16, n Gjymishka A, Kulemina LV, Shenoy V, Katovich MJ, Ostrov DA, Rooted MK Decreased Aceturate is an ACE2 activator and a novel antihypertensive drug FASEB J., v. 24, p. 1,033, 2010).

DIZE is an aromatic diamidine used as a veterinary antiparasitic that has demonstrated significant trypanocidal activity (except for Trypanosoma cruzi) and leishmanicide (Jean-Moreno, Rojas R., Goyeneche D., Coombs GH and Walker J, Leishmania donovani: differential activities of classical topoisomerase inhibitors and antileishmanials against parasite and host cells at the level of DNA topoisomerase I and in cytotoxicity assays. Exp. Parasite /. , v. 1112, p. 21-30, 2006; Kroubi M, Daulouede S, Karembe H, Jallouli Y, Howsam M, Mossalayi D, Vincendeau P, Betbeder D Development of a nanoparticle formulation to treat African trypanosomiasis. Nanotechnology, v. 21, 2010; Wéry M Drug used in the treatment of sleeping sickness (human African trypanosomiasis: HAT). Int. J. Antimicrob. Agents, v.3, p.227-38, 1994). The drug has been used to control trypanosomiasis in animals for over 40 years and, although never approved for human use, has been widely used in Africa to treat diseases caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense (Akpa PO, Ezeokonkwo). RC, Eze CA, Anene BM Comparative efficacy assessment of pentamidine isethionate and diminazene aceturate in the chemotherapy of Trypanosoma brucei brucei infection in dogs Parasito Vet., V. 2-4, pp. 39-49, 2008; Combination chemotherapy of CNS trypanosomiasis, Acta Tropica, v. 54, pp 205-21 3, 1993; Wery M. Drug used in the treatment of sleeping sickness (human African trypanosomiasis: HAT) Int. J. Antimicrob. , v.3, p.227-38, 1994). Some tests with the drug have been performed in humans to prevent encephalopathy in patients with melarsoprol-treated sleeping sickness (African human trypanosomiasis), and the drug has been shown to be rapidly absorbed when given orally and has not shown significant irritation or adverse effects. , even after prolonged exposure (Bailey NM. Oral Berenil in the treatment and prophylaxis of human trypanosomiasis. Trans. R. Soc. Trop. Med. Hyg., v. 62, p. 22, 1968). In contrast, other studies indicate that the use of this substance is limited by its low stability and the toxic effects that may be developed on non-target tissues (Kroubi M, Daulouede S, Karembe H, Jallouli Y, Howsam M, Vinceneau P, Betbeder D. Development of a nanoparticulate formulation of diminazene to treat African trypanosomiasis. Nanotechnology. V. 21, p. 55-120, 201.0). In addition, it is rapidly excreted, having a half-life of only two hours (Jennings FW. Combination chemotherapy of CNS trypanosomiasis. Acta Tropica, v. 54, p. 205-21 3, 1 993). The main toxic effects of the drug are nervous and digestive (Wéry M. Drug used in the treatment of sleeping sickness (human African trypanosomiasis: HAT). Int. J. Antimicrob. Agents, v.3, p.227-38, 1994) . In addition, DIZE has also been associated with silver and has high antitumor activity and lipid nanoparticles containing the drug for potential brain release of the drug in the treatment of sleep sickness (Olbrich C, Gessner A, Schroder W, Kayser O, Muller RH, Olbrich C, Gessner A, Schroder W, Kayser O, MUIIer RH Lipid-drug conjugate nanoparticles of the hydrophilic drug diminishing cytotoxicity testing and mouse serum adsorption J. Control, Release, v.96, p.425-35 , 2004).

 State of the art patent documents describing the use of DIZE for the treatment of cardiovascular and cardiopulmonary diseases, as well as for the treatment of parasitic diseases are available. However, no document deals with its use in the treatment of eye diseases. Regarding xanthenone, nothing was found.

 For example, RU20081 50401 describes a formulation containing DIZE for the treatment of babesiosis.

 WO9428162 describes the use of DIZE in the treatment of chronic trypanosomiasis in humans and other animals.

 WO2008066770 describes pharmaceutical compositions containing DIZE for treating cardiovascular and cardiopulmonary diseases, preferably hypertension and pulmonary injuries.

The use of controlled release systems for drug delivery is an important alternative among known treatment strategies. Demand for controlled release systems for drug delivery has been widely reported in the literature. These systems have the advantage of allowing continuous, constant and prolonged release of the drug, maintaining a stable level of the drug in the patient's body and avoiding adverse effects that could occur compared to conventional administration. Given this, new solid, semi-solid and liquid dosage forms have been developed to meet this need. Examples include liposomes, micro and nanospheres, micro and nanocapsules, coated tablets, transdermal patches and implants, among others. The use of these systems in the treatment of chronic diseases, such as glaucoma and diabetic retinopathy, is even more interesting given that prolonged treatment and the need for frequent use of the drug limit the patient's adherence to treatment. can culminate in the blindness of the individual.

 Considering that no studies were found in the literature that prove the activity of activators of the ECA2 / Ang- (1-7) / Receptor Mas axis in eye diseases and considering the importance of controlled release systems for the treatment of chronic diseases, such as glaucoma, retinopathies and other retinal degenerations, the present technology describes controlled or uncontrolled release pharmaceutical compositions containing ECA2 / Ang- (1-7) / Receptor axis activators and their use for the treatment of eye diseases involving increased IOP and / or degeneration of retinal cells and / or optic nerve.

These pharmaceutical compositions were administered by different routes, evaluating them for the treatment of diseases such as glaucoma and retinopathy, preferably diabetic retinopathy. The results show the potent activity of ECA2 / Ang- (1 -7) / Receptor Mas axis activators in reducing IOP and protecting retinal and optic nerve cells. Several patents describe the use of angiotensin II and ACE antagonists in the treatment of retinopathy and glaucoma (CN 1 01690816, CN 1 01658675, CY2567, US7906501, PI001 0084-6, BRPI0409293), but no document found reports the use of activators. of ECA2.

Brief Description of the Figures

 Figure 1 - Hydration potential of white implants and implants containing the ACE2 activator (DIZE).

 Figure 2 - Infrared absorption spectrum of a model of ECA2 activator (DIZE) (A), white implants (B) and implants containing ECA2 activator (DIZE) (C).

 Figure 3 - Differential exploratory calorimetry curves for a model of ECA2 activator (DIZE), white implants and implants containing ECA2 activator (DIZE) (a, first run; b, second run).

 In the Differential Exploratory Calorimetry (DSC) curves obtained for the implants, the observed and characteristic thermal events of the polymer were water loss at 64.2 ° C (Figure 3A) and its decomposition at 314 ° C (Figure 3B). For the ECA2 activator, the thermal events of dehydration (92 ° C) and decomposition (214 ° C) were observed. For implants (Figure 3), it was possible to notice a small difference between the

Figure 4 - Side scan electron micrographs of white implants (a) and implants containing ACE2 activator (DIZE) (b).

Figure 5 - In vitro release profile for implants containing ECA2 activator (DIZE).

Figure 6 - Comparison of IOP values between control group (normal animals) and glaucoma group (animals with induced glaucoma), both subdivided into untreated and ECA2 activator-treated (DIZE) treated animals as oral solution (gavage). Study period: 4 weeks. Initiation of treatment: after first induction. End of treatment: after 4 weeks. * p <0.05 vs. Untreated control. #p <0.05 vs. Untreated Glaucoma Figure 7 - Comparison of mean blood pressure values between control group (normal animals) and glaucoma group (animals with induced glaucoma), both subdivided into untreated animals and ECA2 activator-treated (DIZE) treated animals. oral (gavage). Study period: 4 weeks. Initiation of treatment: after first induction. End of treatment: after 4 weeks.

 Figure 8 - Comparison between retinal ganglion cell (Cg) morphometric data of control group (normal animals) and glaucoma group (animals with induced glaucoma), both subdivided into untreated animals and animals activated with ECA2 (SAYS) in the form of oral solution (gavage). Study period: 4 weeks. Initiation of treatment: after first induction. End of treatment: after 4 weeks.

Figure 9 - IOP of normal animals (control group) and with induced glaucoma (glaucoma group) when treated with ECA2 activator (DIZE) in the form of eye drops (instillation), compared with normal animals (control group) and with induced glaucoma ( glaucoma group) untreated. Study period: 4 weeks. Initiation of treatment: after first induction. End of treatment: after 4 weeks * p <0.001 vs. Untreated control. #p <0.001 vs. untreated glaucoma.

Figure 10 - Systemic blood pressure of normal animals (control group) and induced glaucoma (glaucoma group) when treated with ECA2 activator (DIZE) as eye drops (instillation) compared to normal animals (control group) and glaucoma. induced (glaucoma group) untreated. Study period: 4 weeks. Initiation of treatment: after first induction. End of treatment: after 4 weeks.

Figure 11 - IOP of normal (control group) and induced glaucoma (glaucoma group) animals when treated with the eye receptor activator But in the form of eye drops (instillation), compared to animals with untreated induced glaucoma (glaucoma group). Study period: 1 week. Beginning of treatment: after first induction. End of treatment: 1 week. * p <0.05 vs. Control. #p <0.05 vs. Untreated glaucoma.

 Figure 12 - IOP of normal animals (control group) and induced glaucoma (glaucoma group) when treated with ECA2 activator (DIZE) in the form of eye drops (instillation), compared to normal animals (control group) and induced glaucoma ( glaucoma group) untreated. Study period: 5 weeks. Beginning of treatment (first arrow on graph): after second induction. End of treatment (second arrow on graph): before fourth induction. * p <0.001 vs. untreated control. #p <0.001 vs. untreated glaucoma.

Figure 13 - Systemic blood pressure of normal (control group) and induced glaucoma (glaucoma group) animals when treated with eye drop activator (DIZE) in the form of eye drops (instillation) compared to normal animals (control group) and glaucoma induced (glaucoma group) untreated. Study period: 5 weeks. Beginning of treatment: after the second induction. End of treatment: before the fourth induction.

 Figure 14 - IOP of normal (C) and induced glaucoma (G) animals when treated with ECA2 activator (DIZE) in the form of eye drops (instillation) with or without Mas A-779 receptor blocker compared to normal animals (control group) and with induced glaucoma (glaucoma group) not treated or treated with Mas receptor only. Study period: 3 weeks. Initiation of treatment with ECA2 activator and / or Mas receptor blocker (black arrow): after first induction. End of treatment: 3 weeks. * p <0.001 vs. untreated control. #p <0.001 vs. treated glaucoma + A-779.

Figure 15 - IOP of normal animals (control group) and with induced glaucoma (glaucoma group) when treated with implant-activated ECA2 activator (DIZE) compared to normal animals (control group) and induced glaucoma (glaucoma group) not treated. Study period: 5 weeks. Initiation of treatment: after the second induction. End of treatment: before the fourth induction. * p <0.001 vs. untreated control. #p <0.001 vs. untreated glaucoma. Figure 16 - Systemic arterial blood pressure of normal animals (control group) and induced glaucoma (glaucoma group) when treated with an ACE2 activator (DIZE) as an implant compared to normal animals (control group) and induced glaucoma (group untreated glaucoma). Study period: 5 weeks. Initiation of treatment: after the second induction. End of treatment: before the fourth induction.

 Figure 17 - IOP of normal animals (graph B) and animals with induced glaucoma (graph A) when treated with the ECA2 activator (DIZE) in the form of eye drops (instillation) and in the implant form, compared to untreated and non-treated animals. with animals treated with white implants. Study period: 5 weeks. Initiation of treatment: after the second induction. End of treatment: before the fourth induction.

 Figure 18 - Retinal ganglion cell (Cg) morphometry in diabetic animals treated with ECA2 activator (XNT) as oral solution (gavage) compared to untreated diabetic animals. Study period: 7 weeks. Initiation of treatment: after the second week. End of treatment: seventh week.

Detailed Description of Technology

The present invention describes different pharmaceutical compositions containing ECA2 / Ang- (1-7) / Mas receptor activators, preferably ECA2 activators, for example DIZE and XNT, and Mas receptor activators such as HP CD / Ang. - (1-7). It also describes their use in the treatment of eye disorders related to increased IOP and / or retinal and / or optic nerve degeneration, such as glaucoma and retinopathies, preferably diabetic retinopathy. The mentioned ECA2 / Ang- (1-7) / Receptor axis activators have been administered in conventional and extended release pharmaceutical compositions in the treatment of experimental hyauronic acid-induced glaucoma in rats and in the treatment of diabetic retinopathy. These activators caused potent IOP reduction in animals with induced glaucoma. In addition, activation of this axis reduced retinal cell degeneration in rats with retinopathy due to induced DM.

 Pharmaceutical compositions which may be used for the delivery of ECA2 / Ang- (1-7) / Receptor Shaft Activators include, but are not limited to, conventional pharmaceutical compositions such as solutions, suspensions, tablets, gels, creams, capsules ( hard or gelatinous), emulsions, lotions, among others, and unconventional pharmaceutical compositions such as implants, micro or nanocapsules, micro or nanospheres, micro or nanoemulsions, liposomes, among others, whether they consist of any raw materials (for example, (lipid or mixed), with or without controlled release of ECA2 / Ang- (1-7) / Such pharmaceutical compositions may be administered orally, topically, intraocularly, intraocularly, periocularly, conjunctivally or intravenously, among others.

 The invention may be better understood without limitation from the following examples. In these examples, XNT and DIZE were used as the ECA2 activator model, HPpCD / Ang- (1-7) was used as the Mas Receiver activator model, and the A-779 was used as the Mas Receiver blocker model. .

Example 1 - Obtaining and Characterization of Pharmaceutical Compositions Containing ECA2 Activators and Mas Receptor Activators

As examples of formulations for delivery of ECA2 activators, conventional pharmaceutical forms have been developed. (oral solutions and eye drops) and implants for controlled drug release.

 Oral solutions were obtained by diluting the ECA2 activators and the Receptor Mas activator in distilled water or another pharmacologically acceptable excipient. Adjuvants such as preservatives, antioxidants, solubilizers, colorants, flavors, flavorings, sugars, viscous, sweeteners, chelators, pH correctors, among others, may be used. Other oral dosage forms (such as tablets, capsules, suspensions and syrups) may also be used. The oral solutions were clear and had a pH between 5.0 and 10.0, preferably between 6.0 and 9.0.

 The eye drops were prepared by diluting the ECA2 activator or Mas receptor activator in pharmacologically acceptable excipient. Isotonizers (eg NaCl, Glycerol, Glucose), buffering agents (eg phosphorus and sulfate salts), pH correctors (eg HCl, NaOH), viscous, antioxidant, chelating and preservative, among others, may also be used. Eye drops were sterilized and isotonia and pH were adjusted before use. The pH was between 5.0 and 10, preferably between 6.0 and 9.0. Other pharmaceutical forms such as suspensions, ophthalmic ointments, gels, hydrogels and emulsions may also be used for topical drug delivery.

As examples of the use of the ECA2 activator in controlled release systems, polymeric implants were developed. To obtain the implants, the polymer was dispersed in an aqueous solution containing ECA2 activator (when necessary, acid was used to promote polymer dispersion). The obtained dispersion was stirred to obtain a gel. This gel was spread on a smooth metallic, polymeric, glassy or ceramic surface, preferably polymeric, such as silicone plates, and allowed to dry to obtain the implants. Drying can be performed at room temperature or under heating. Multilayer implants can also be obtained by repeating the same procedure. After drying the first layer, solutions previously prepared as described for the first layer are spread over it and dried. This process can be repeated several times (between one and ten times, on average 3 times) to obtain the multilayer implants. ECA2 activator-containing layers of the multilayer devices may or may not be layered without layers (white). The number of white layers in the device ranges from 0 to n-1, where n is the number of device layers. The order of distribution of layers is variable. Any distribution combination can be accepted. Distributions that allow ECA2 activator layers to be in the center and layers without ECA2 activator to be at the ends of implants are preferred.

 To obtain the devices, when acid addition is required for polymer solubilization, inorganic acid, preferably HCl, H3PO4, H2SO4, or organic acid, preferably acetic acid, may be used. The polymer concentration may range from 0.5 to 20% of the gel, preferably from 1 to 5%. The final concentration of the ECA2 activator may range from 0.01 to 99% of the dry device weight, preferably from 0.1 to 30%. The acid concentration may range from 0.5 to 50%. The agitation time of the gel may vary from seconds to one week, preferably one or two days. The stirrer used may be of any type. Drying can be done up to 40 ° C.

The polymer employed to obtain the implants may be natural, preferably selected from the group comprising celluloses, gums, exudates, gelatin, keratin, alginates, galactomannans, chitosans or their derivatives methyl, hydroxypropyl, acetophthalate, acetate, methoxy, hydropropoxy, acetophthalyl, carboxy carboxymethyl, thio, whether or not hydrolyzed, or their salts of Li, Na, K, Ca, Mg, Al, Zn, Fe, Cu, Ni, alone, or in combination or in the form of copolymers; or synthetic, preferably selected from the group comprising acrylic acid derivatives, preferably polyacrylate, polymethyl methacrylate, polyethylacrylate or polyethyl methacrylate, acid derivatives glycolic acid derivatives, hydrophilic or hydrophobic caprolactone derivatives, biodegradable or non-biodegradable.

 Table 1 shows an example of gel formulation used to obtain the implants. Table 1: Gel Composition for Obtaining ECA2 Activator Implants

 Table 2 shows an example of gel composition for implants without ECA2 activator.

Table 2: Gel composition for obtaining layers without activator of

ECA2 (white).

 The implants obtained after drying of the formulations were further characterized.

 In the hydration potential analyzes, an increase in the hydration potential of the implants was observed due to the addition of the

ECA2, suggesting that this substance is able to disrupt the formed polymeric matrix, in order to increase the water uptake by the implant.

(Figure 1).

In the absorption spectra in the infrared region (Figure 2), the band characteristics of the polymer absorption (3256 cm ^"1, 1633 ^{cm" 1,} 1539 cm ^"1, 1064 ^{cm" 1,} 1022cm ^"1, 896 ^{cm" 1)} were preserved in implants containing the ACE2 activator without significant position displacement, suggesting that there was no reaction of the polymer with the ECA2 activator. On the other hand, characteristic bands of the ECA2 activator (such as the 1263 cm- ¹ band) were also identified in the implant containing it, suggesting that this substance was efficiently incorporated into the implant.

 In the Differential Exploratory Calorimetry (DSC) curves obtained for the implants, the observed and characteristic thermal events of the polymer were water loss at 64.2 ° C (Figure 3A) and its decomposition at 314 ° C (Figure 3B). For the ECA2 activator, the thermal events of dehydration (92 ° C) and decomposition (214 ° C) were observed. For implants (Figure 3), it was possible to notice a slight difference between decomposition temperatures without ECA2 activator (white) and with ECA2 activator (from 314 to 297.5 ° C), which could indicate a disturbance in the structure. of the polymer associated with the presence of the activator of ECA2, corroborating the results obtained in the hydration test. The peak associated with the degradation of the ECA2 activator, on the other hand, cannot be evidenced on the implant-bearing DSC curve, suggesting that the ECA2 activator was in an amorphous, molecularly dispersed state or as a solid solution in the implant. implantation.

 By scanning electron micrographs (Figure 4), it was observed that the implants are uniform in size and do not have granular particles inside, suggesting that the ECA2 activator interacted with the polymer matrix and is dispersed in the matrix, confirming the results obtained in the DSC analysis.

The in vitro release profile of the implant was evaluated by dipping the devices in PBS buffer. After predetermined stirring times at a controlled temperature, all medium was removed and a new volume of medium was added to the implants. The ECA2 activator present in the removed medium was dosed by a validated quantitation method (ultraviolet or visible absorption spectrophotometry, detector-coupled high performance liquid chromatography or mass spectrometer, gas-coupled gas chromatography). mass spectrometer, titration, or other suitable method, defined in accordance with ECA2 activator used). About 70% release of the implant ECA2 activator can be observed within the first two hours of the experiment. The remainder was not released even after 8 hours of study, suggesting an implant potential for controlled drug release (Figure 5).

 Other extended release pharmaceutical forms such as micro and nanospheres, micro and nanocapsules, micro and nano emulsions and liposomes may be developed.

 The administration of ECA2 activators and Mas receptor activators for the treatment of eye disorders has yet to be performed by other routes such as intravenous, intravitreal, periocular, intraocular, subconjunctival, intramuscular and subcutaneous. Thus, other controlled or uncontrolled release formulations, such as injectable solutions, suspensions and emulsions may be produced, provided that pharmaceutically acceptable excipients are used. Example 2 - Glaucoma Induction and IOP Measurement

 Unilateral glaucoma was induced in the right eye of rats by injecting 30μΙ_ of hyaluronic acid (10mg / ml_) in the anterior chamber near the horny scleral limb once a week for 1 to 6 weeks, preferably 3 to 5 weeks. , always on the same day and time, following the protocol of Moreno et al., 2005 (Moreno MC, Marcos BHJA, Croxatto CJO, Sandea PH, Campanellia J, Jaliffaa CO, Benozzia J, Rosensteina RE. A new experimental model of glaucoma in rats through intracameral injections of hyaluronic acid (Experimental Eye Research, v. 81, pp. 71-80, 2005). For this, the animals were anesthetized with general anesthetic (eg ketamine (70 mg / kg) exilazine 10 mg / kg) intraperitoneally and local anesthetic (eg 0.4% benoxinate in the cornea. No procedure was performed in left eye, which was used as a control group.

During induction and treatment of glaucoma, either with the ACE2 activator, or Mas receptor activator, or Mas receptor inhibitor, IOP was measured weekly, always the day before the next induction. For this we used a tonometer [eg TonoPen XL (Mentor, Norwell, MA)]. The measurement was performed on non-sedated animals contained gently with a small towel. At each measurement, three IOP readings (with a standard error of less than 10%) were obtained in each eye, and the mean of these three measurements was considered to be the corresponding IOP value for that day. Example 3 - Activity of the pharmaceutical composition containing orally administered ECA2 activators.

To evaluate the activity of pharmaceutical compositions containing ECA2 activators used orally to prevent the development of retinal and optic nerve cell and IOP lesions, the animals underwent unilateral glaucoma induction surgery once a week, for 4 weeks. IOP measurements were also performed weekly for 4 weeks on the day before the next induction. Animals were treated daily with oral solution containing ECA2 activator by gavage. The treatment began immediately after the first induction and lasted for 4 weeks.

 The IOP of the treated glaucoma (GT) group was significantly lower than that of the untreated glaucoma (GNT) group during the four weeks of ECA2 activator administration (Figure 6). In addition, it was observed that the GT group was not statistically different from the untreated control group (CNT) at all 4 weeks. The results indicate that the ACE2 activator is a potent oculus-hypotensive, verifying its ability to prevent IOP increase and, consequently, its preventive action in glaucoma.

Regarding the mean arterial pressure (MAP) of these animals, no significant difference was found between animals treated and not treated with ACE2 activator during the entire experimental period, indicating that this group of substances is capable of reducing IOP without interfering with MAP ( Figure 7). Morphometric analysis (Figure 8) suggests that treatment with ACE2 activator also attenuates glaucoma complications, since the number of ganglion cells (Cg) in the GNT group was significantly lower than the GT group, which is indicative of more pronounced cell death in the GNT group. Example 4 - Activity of the conventional pharmaceutical composition containing ECA2 activators or topically Mas receptor activators applied from the first induction of glaucoma.

Activity of conventional pharmaceutical compositions containing ECA2 activators used topically to prevent the development of retinal and optic nerve cell and IOP lesions was evaluated by using eye drops containing ECA2 activator or Mas receptor activator in the treatment of animals. with unilateral glaucoma induced once a week for 4 weeks. IOP measurements were also performed weekly for 4 weeks on the day before the next induction. The animals were treated by instillation. The treatment began immediately after the first induction and lasted for 4 weeks.

 Similar to the results obtained with oral (systemic) treatment, it was also observed in the local treatment (Figure 9) that the instillation of the ACE2 activator prevented the increase of the IOP of the GT group, and the values were significantly lower. than the GNT group in all 4 weeks of simultaneous induction and instillation of the ECA2 activator. There was no significant difference in MAP between animals treated and not translated with ACE2 activator, again demonstrating that ACE2 activator did not alter systemic blood pressure (Figure 10).

 Similar results were obtained for the use of Mas receptor activator eye drops: the IOP of the GT group was significantly lower than that of the GNT group after administration of the Mas receptor activator (Figure 11). The results indicate that the ECA2 / Ang- (1-7) / Receptor Mas axis activators are potent oculhohypertensive and antiglaucoma agents.

Example 5 - Activity of conventional pharmaceutical composition containing topical ECA2 activators applied after the second induction of glaucoma.

The evaluation of the activity of conventional formulations containing ACE2 activators in the treatment of glaucoma was performed by induction of unilateral glaucoma once a week for 5 weeks. IOP measurements were also performed weekly for 5 weeks on the day before next induction. The location and daily treatment with eye drops containing ACE2 activator started after the second induction, that is, after confirming the elevated IOP. The treatment lasted for 15 days. After this period, the animals continued to undergo weekly induction for a further 2 weeks, but did not receive treatment.

It was found that the ACE2 activator was able to reduce the IOP of the GT group, whose values returned to baseline levels. Furthermore, the interruption treatment resulted in increased IOP group GT which, from this moment, spent not be different from NTG (GT - week 5 31 ± 2.0 mmHg vs. GNT - 5 week: 26.4 ± 2.1 mmHg) (Figure 12). Regarding MAP, no difference was observed between animals treated and not treated with ACE2 activator (Figure 13).

Example 6 - Blocking the activity of the conventional formulation containing ECA2 activators in reducing IOP by inhibiting the Mas receptor.

The importance of the ECA2 / Ang- (1-7) / receptor Mas axis in reducing IOP was verified by treating animals with Mas receptor blocker glaucoma. For this, unilateral glaucoma was induced once a week for 3 weeks. IOP measurements were also performed weekly for 3 weeks on the day before the next induction. The animals were treated with eye drops containing ECA2 activator. The treatment began immediately after the second induction and lasted for 2 weeks. Concurrently, after the second induction were implanted osmotic pumps subcutaneously containing But receptor blocker.

 When using the Mas receptor blocker, it was found that the action of the ECA2 activator was totally blocked, and the GT + blocker group was not statistically different from the GNT group. In addition, the IOP of the GT + receptor blocker group But was significantly different from the unblocked GT group (Figure 14).

This result indicates that the action of ECA2 activators and Mas receptor activators in the treatment of glaucoma is related to ECA2 / Ang- (1-7) / receptor axis activation But not with other physicochemical or pharmacological characteristics of the prototypes used.

Example 7 - Activity of controlled release pharmaceutical composition containing topical ECA2 activators in reducing IOP.

The activity of the extended release pharmaceutical compositions containing ECA2 activator described in Example 1 was evaluated by induction of unilateral glaucoma once a week for 5 weeks. IOP measurement was also performed weekly for 5 weeks on the day before the next induction. The animals received a polymeric implant for controlled release of ACE2 activator, which was implanted into the conjunctival sac of animals after the confirmation of elevated IOP (2 after induction). The animals remained with the implant until the end of treatment. As negative control of this experiment, the white implants (also implanted immediately after the second induction) were evaluated. As a positive control, treatment by instillation of a solution containing ACE2 activator was considered. Treatment with the solution was also started immediately after the second induction and maintained daily for fifteen days.

Results showed that after confirmation of elevated IOP for one week (28.8 ± 4.3 mmHg), the implant placed in the conjunctival sac at a concentration equivalent to the dose used for single-day instillation in prevention and treatment protocols. site, was able to reduce IOP for 1 month (week 5: 10.4 ± 0.9 mmHg) (Figure 15). The MAP of the animals of this protocol treated and untreated with ECA2 activator once again was not significantly different (Figure 16).

As can be seen in Figure 17, while IOP in all groups remained elevated after the first induction, a significant reduction in IOP was observed in the groups treated with either the ECA2 activator implant or the ECA2 activator implant. eye drops. For animals treated with the eye drops, an increase in pressure was observed after the end of instillation, while IOP remained low at four weeks after implant treatment, indicating that the devices are capable of releasing ECA2 activator to keep the IOP under control for at least one month. On the other hand, white implants were not able to reduce IOP, which corroborates the IOP-lowering activity associated with the ACE2 activator. Example 8 - Activity of conventional pharmaceutical composition containing ECA2 activators in diabetic retinopathy

 Diabetes was induced by injecting streptozotocin (50mg / kg) into the penile vein of fasting rats. After confirmation of diabetes on the tenth day, the rats were treated orally (gavage) with the ACE2 activator for 30 days. Next, the eyes were enucleated, fixed in 4% Bouin and processed for imbibition and inclusion in Paraplast. Analyzes were performed by morphometry in histological sections stained with H&E and immunohistochemistry. The results showed that ECA2 is expressed in the following retinal layers: pigmented epithelium (Ep), photoreceptors, external and internal plexiform cells and ganglion cells (Cg). ECA2 activator treatment increased ECA2 expression in these layers in both normal and diabetic rats. In addition, treatment of diabetic rats with the ACE2 activator mitigated the reduction in retinal Cg number compared to untreated diabetic animals (575 ± 16 vs. 477 ± 54 cells). These findings suggest that ACE2 plays an important role in the early stages of diabetic retinopathy and that treatment with ACE2 / Ang- (1-7) / Receptor axis activators may be an important therapeutic strategy in the management of diabetic retinopathy (Figure 18 ).

Claims

 PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF EYE PATHOLOGIES characterized by comprising ECA2 / Ang- (1-7) / receptor Mas activators and pharmacologically acceptable excipients.

 2. PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF EYE PATHOLOGIES according to claim 1, characterized by the axis activator ECA2 / Ang- (1-7) / receptor But being an activator of ECA2.

 3- PHARMACEUTICAL COMPOSITIONS FOR TREATMENT

EYE PATHOLOGIES according to claims 1 and 2, characterized in that the ECA2 activator is diminazene (in free base or salt form, preferably aceturate) and its analogs, or XNT (1 - [(2-dimethylamino) ethylamino] -4- (hydroxymethyl) -7 - [(4-methylphenyl) sulfonyloxy] -9 xanthen-9-one) and its analogs, or resorcinoinaphthaline and its analogs.

 PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF EYE PATHOLOGIES according to claim 1, characterized in that the ECA2 / Ang- (1-7) / receptor axis activator Mas is a Mas receptor activator.

 PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF EYE PATHOLOGIES according to claims 1 and 4, characterized in that the receptor activator Mas is H PpCD / Ang- (1-7) and its analogues.

 6- PHARMACEUTICAL COMPOSITIONS FOR TREATMENT

EYE PATHOLOGIES according to claims 1 - 5, characterized in that they are in the form of solution, suspension, emulsion, capsule (hard or gelatinous), tablet, gel, cream, lotion, implant, microcapsule, nanocapsule, nanosphere, microsphere, nanoemulsion. , microemulsion and / or liposomes.

PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF EYE PATHOLOGIES according to claims 1-6, characterized by oral, topical, intraocular, periocular, conjunctival or intravenous administration.

 PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF EYE PATHOLOGIES according to claims 1-7, characterized in that the ECA2 / Ang- (1 - 7) / receptor axis activator release is conventional or prolonged.

 PHARMACEUTICAL COMPOSITIONS FOR TREATING EYE PATHOLOGIES according to claims 1-8, characterized in that the conventional pharmaceutical form is an oral solution or an eye drop.

 PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF EYE PATHOLOGIES according to claims 1-8, characterized in that the extended release dosage form is a polymeric implant.

 1 1 - PHARMACEUTICAL COMPOSITIONS FOR TREATMENT

EYE PATHOLOGIES according to claim 10, characterized in that the polymers are natural or synthetic.

 Pharmaceutical compositions for the treatment of eye diseases according to claims 10 and 11, characterized in that the natural polymers are selected from the group comprising celluloses, gums, exudates, gelatin, keratin, alginates, galactomannans, chitosans or their methyl derivatives. hydroxypropyl, acetophthalate, acetate, methoxy, hydropropoxy, acetophthalyl, whether or not hydrolyzed or their salts of Li, Na, K, Ca, Mg, Al, Zn, Fe, Cu, Ni, isolated, in combination or as copolymers .

 PHARMACEUTICAL COMPOSITIONS FOR TREATING EYE PATHOLOGIES according to claims 10 and 11, characterized in that the synthetic polymers are acrylic acid derivatives, lactic acid derivatives, glycolic acid derivatives and / or caprolactone derivatives.

PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF EYE PATHOLOGIES according to claims 10, 11 and 13, characterized in that the synthetic polymers derived from acrylic acid are preferably polyacrylate, polymethyl methacrylate, polyethylacrylate and / or polyethyl methacrylate.

 PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF EYE PATHOLOGIES according to claims 10

14, characterized in that the polymer concentration is from 0.5 to 20%, preferably from 1 to 5%.

 PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF EYE PATHOLOGIES according to claims 1 to 15, characterized by the axis activator ECA2 / Ang- (1-7) / receptor. But being present at a concentration between 0.01 to 50% of the device, preferably from 0.1 to 30%.

 Use of pharmaceutical compositions for treating ocular pathologies according to claims 1 to 16, characterized in that they are in the treatment of conditions related to increased IOP and / or retinal and / or optic nerve degeneration.

 Use of the pharmaceutical compositions for treating ocular pathologies according to claim 17, characterized in that they are preferably for the treatment of glaucoma and retinopathies.

 Use of pharmaceutical compositions for treating ocular pathologies according to claim 17, characterized in that retinopathy is preferably diabetic retinopathy.